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Results for “protein folding”

Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 145 records · Page 8
All sourcesNASA NTRSDOE OSTI
DOE OSTI2023

Improving AlphaFold2-based protein tertiary structure prediction with MULTICOM in CASP15

Since the 14th Critical Assessment of Techniques for Protein Structure Prediction (CASP14), AlphaFold2 has become the standard method for protein tertiary structure prediction. One remaining challenge is to further improve its prediction. We developed a new version of the MULTICOM system to sample diverse multiple sequence alignments (MSAs) and structural templates to improve the input for AlphaFold2 to generate structural models. The models are then ranked by both the pairwise model similarity and AlphaFold2 self-reported model quality score. The top ranked models are refined by a novel structure alignment-based refinement method powered by Foldseek. Moreover, for a monomer target that is a subunit of a protein assembly (complex), MULTICOM integrates tertiary and quaternary structure predictions to account for tertiary structural changes induced by protein-protein interaction. The system participated in the tertiary structure prediction in 2022 CASP15 experiment. Our server predictor MULTICOM_refine ranked 3rd among 47 CASP15 server predictors and our human predictor MULTICOM ranked 7th among all 132 human and server predictors. The average GDT-TS score and TM-score of the first structural models that MULTICOM_refine predicted for 94 CASP15 domains are ~0.80 and ~0.92, 9.6% and 8.2% higher than ~0.73 and 0.85 of the standard AlphaFold2 predictor respectively.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

On the advantages of exploiting memory in Markov state models for biomolecular dynamics

Biomolecular dynamics play an important role in numerous biological processes. Markov State Models (MSMs) provide a powerful approach to study these dynamic processes by predicting long time scale dynamics based on many short molecular dynamics (MD) simulations. In an MSM, protein dynamics are modeled as a kinetic process consisting of a series of Markovian transitions between different conformational states at discrete time intervals (called “lag time”). To achieve this, a master equation must be constructed with a sufficiently long lag time to allow interstate transitions to become truly Markovian. This imposes a major challenge for MSM studies of proteins since the lag time is bound by the length of relatively short MD simulations available to estimate the frequency of transitions. Here, we show how one can employ the generalized master equation formalism to obtain an exact description of protein conformational dynamics both at short and long time scales without the time resolution restrictions imposed by the MSM lag time. Using a simple kinetic model, alanine dipeptide, and WW domain, we demonstrate that it is possible to construct these quasi-Markov State Models (qMSMs) using MD simulations that are 5–10 times shorter than those required by MSMs. These qMSMs only contain a handful of metastable states and, thus, can greatly facilitate the interpretation of mechanisms associated with protein dynamics. A qMSM opens the door to the study of conformational changes of complex biomolecules where a Markovian model with a few states is often difficult to construct due to the limited length of available MD simulations.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2021

Computationally designed peptide macrocycle inhibitors of New Delhi metallo-β-lactamase 1

The rise of antibiotic resistance calls for new therapeutics targeting resistance factors such as the New Delhi metallo-β-lactamase 1 (NDM-1), a bacterial enzyme that degrades β-lactam antibiotics. We present structure-guided computational methods for designing peptide macrocycles built from mixtures of l - and d -amino acids that are able to bind to and inhibit targets of therapeutic interest. Our methods explicitly consider the propensity of a peptide to favor a binding-competent conformation, which we found to predict rank order of experimentally observed IC 50 values across seven designed NDM-1- inhibiting peptides. We were able to determine X-ray crystal structures of three of the designed inhibitors in complex with NDM-1, and in all three the conformation of the peptide is very close to the computationally designed model. In two of the three structures, the binding mode with NDM-1 is also very similar to the design model, while in the third, we observed an alternative binding mode likely arising from internal symmetry in the shape of the design combined with flexibility of the target. Although challenges remain in robustly predicting target backbone changes, binding mode, and the effects of mutations on binding affinity, our methods for designing ordered, binding-competent macrocycles should have broad applicability to a wide range of therapeutic targets.

42 ENGINEERING↗
DOE OSTI2023

Crystal structure of the kinase domain of a receptor tyrosine kinase from a choanoflagellate, Monosiga brevicollis

Genomic analysis of the unicellular choanoflagellate, Monosiga brevicollis (MB), revealed the remarkable presence of cell signaling and adhesion protein domains that are characteristically associated with metazoans. Strikingly, receptor tyrosine kinases, one of the most critical elements of signal transduction and communication in metazoans, are present in choanoflagellates. We determined the crystal structure at 1.95 Å resolution of the kinase domain of the M . brevicollis receptor tyrosine kinase C8 (RTKC8, a member of the choanoflagellate receptor tyrosine kinase C family) bound to the kinase inhibitor staurospaurine. The chonanoflagellate kinase domain is closely related in sequence to mammalian tyrosine kinases (~ 40% sequence identity to the human Ephrin kinase domain EphA3) and, as expected, has the canonical protein kinase fold. The kinase is structurally most similar to human Ephrin (EphA5), even though the extracellular sensor domain is completely different from that of Ephrin. The RTKC8 kinase domain is in an active conformation, with two staurosporine molecules bound to the kinase, one at the active site and another at the peptide-substrate binding site. To our knowledge this is the first example of staurospaurine binding in the Aurora A activation segment (AAS). We also show that the RTKC8 kinase domain can phosphorylate tyrosine residues in peptides from its C-terminal tail segment which is presumably the mechanism by which it transmits the extracellular stimuli to alter cellular function.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1997

Environmental modification of yield and nutrient composition of 'Waldmann's Green' leaf lettuce

Leaf number, dry weight, and nutrient composition of Lactuca sativa L. cv. Waldmann's Green leaves were compared following 9 days of treatment in a controlled environment room under various combinations of photosynthetic photon flux (PPF:350 vs 800 micromoles m-2 s-1), atmospheric CO2 level (ambient vs 1500 micromoles mol-1), and single-strength (1X:15 mM) vs double-strength (2X:30 mM) nitrogen (N) as NO3- alone or as NH4(+) + NO3- (1:5 molar ratio). CO2 enrichment greatly enhanced leaf number under all PPF and N conditions, but increased leaf dry weight only at high PPF. Conditions favoring high photosynthesis enhanced leaf starch content 3-fold, and protein content increased as much as 64% with 2X NH4(+)+NO3-. Free sugar content was 6 to 9% of leaf dry weight for all treatment combinations, while fat was 1.5 to 3.5%. Ash content varied from 15 to 20% of leaf dry weight. Modified controlled environments can be used to enhance the nutritional content as well as the yield of crops to be used for life support in space-deployed, self-sustaining human habitats. Leaf lettuce is a useful model crop for demonstrating the potential of nutritional value added by environmental manipulation.

Non-NASA Center↗
NASA NTRS1999

Proteolytic dissection of Zab, the Z-DNA-binding domain of human ADAR1

Zalpha is a peptide motif that binds to Z-DNA with high affinity. This motif binds to alternating dC-dG sequences stabilized in the Z-conformation by means of bromination or supercoiling, but not to B-DNA. Zalpha is part of the N-terminal region of double-stranded RNA adenosine deaminase (ADAR1), a candidate enzyme for nuclear pre-mRNA editing in mammals. Zalpha is conserved in ADAR1 from many species; in each case, there is a second similar motif, Zbeta, separated from Zalpha by a more divergent linker. To investigate the structure-function relationship of Zalpha, its domain structure was studied by limited proteolysis. Proteolytic profiles indicated that Zalpha is part of a domain, Zab, of 229 amino acids (residues 133-361 in human ADAR1). This domain contains both Zalpha and Zbeta as well as a tandem repeat of a 49-amino acid linker module. Prolonged proteolysis revealed a minimal core domain of 77 amino acids (positions 133-209), containing only Zalpha, which is sufficient to bind left-handed Z-DNA; however, the substrate binding is strikingly different from that of Zab. The second motif, Zbeta, retains its structural integrity only in the context of Zab and does not bind Z-DNA as a separate entity. These results suggest that Zalpha and Zbeta act as a single bipartite domain. In the presence of substrate DNA, Zab becomes more resistant to proteases, suggesting that it adopts a more rigid structure when bound to its substrate, possibly with conformational changes in parts of the protein.

Non-NASA Center↗
DOE OSTI2024

Water, Solute, and Ion Transport in De Novo-Designed Membrane Protein Channels

Biological organisms engineer peptide sequences to fold into membrane pore proteins capable of performing a wide variety of transport functions. Synthetic de novo-designed membrane pores can mimic this approach to achieve a potentially even larger set of functions. Here, in this work, we explore water, solute, and ion transport in three de novo designed β-barrel membrane channels in the 5–10 Å pore size range. We show that these proteins form passive membrane pores with high water transport efficiencies and size rejection characteristics consistent with the pore size encoded in the protein structure. Ion conductance and ion selectivity measurements also show trends consistent with the pore size, with the two larger pores showing weak cation selectivity. MD simulations of water and ion transport and solute size exclusion are consistent with the experimental trends and provide further insights into structure–function correlations in these membrane pores.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Structural basis of tRNA recognition by the widespread OB fold

The widespread oligonucleotide/oligosaccharide-binding (OB)-fold recognizes diverse substrates from sugars to nucleic acids and proteins, and plays key roles in genome maintenance, transcription, translation, and tRNA metabolism. OB-containing bacterial Trbp and yeast Arc1p proteins are thought to recognize the tRNA elbow or anticodon regions. Here we report a 2.6 Å co-crystal structure of Aquifex aeolicus Trbp111 bound to tRNA Ile , which reveals that Trbp recognizes tRNAs solely by capturing their 3' ends. Structural, mutational, and biophysical analyses show that the Trbp/EMAPII-like OB fold precisely recognizes the single-stranded structure, 3' terminal location, and specific sequence of the 3' CA dinucleotide — a universal feature of mature tRNAs. Arc1p supplements its OB – tRNA 3' end interaction with additional contacts that involve an adjacent basic region and the tRNA body. This study uncovers a previously unrecognized mode of tRNA recognition by an ancient protein fold, and provides insights into protein-mediated tRNA aminoacylation, folding, localization, trafficking, and piracy.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Cell-free Scaled Production and Adjuvant Addition to a Recombinant Major Outer Membrane Protein from Chlamydia muridarum for Vaccine Development

Subunit vaccines offer advantages over more traditional inactivated or attenuated whole-cell-derived vaccines in safety, stability, and standard manufacturing. To achieve an effective protein-based subunit vaccine, the protein antigen often needs to adopt a native-like conformation. This is particularly important for pathogensurface antigens that are membrane-bound proteins. Cell-free methods have been successfully used to produce correctly folded functional membrane protein through the co-translation of nanolipoprotein particles (NLPs), commonly known as nanodiscs. This strategy can be used to produce subunit vaccines consisting of membrane proteins in a lipid-bound environment. However, cell-free protein production is often limited to small scale (<1 mL). The amount of protein produced in small-scale production runs is usually sufficient for biochemical and biophysical studies. However, the cell-free process needs to be scaled up, optimized, and carefully tested to obtain enough protein for vaccine studies in animal models. Other processes involved in vaccine production, such as purification, adjuvant addition, and lyophilization, need to be optimized in parallel. This paper reports the development of a scaled-up protocol to express, purify, and formulate a membrane-bound protein subunit vaccine

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

AI-accelerated protein-ligand docking for SARS-CoV-2 is 100-fold faster with no significant change in detection

Protein-ligand docking is a computational method for identifying drug leads. The method is capable of narrowing a vast library of compounds down to a tractable size for downstream simulation or experimental testing and is widely used in drug discovery. While there has been progress in accelerating scoring of compounds with artificial intelligence, few works have bridged these successes back to the virtual screening community in terms of utility and forward-looking development. We demonstrate the power of high-speed ML models by scoring 1 billion molecules in under a day (50 k predictions per GPU seconds). We showcase a workflow for docking utilizing surrogate AI-based models as a pre-filter to a standard docking workflow. Our workflow is ten times faster at screening a library of compounds than the standard technique, with an error rate less than 0.01% of detecting the underlying best scoring 0.1% of compounds. Our analysis of the speedup explains that another order of magnitude speedup must come from model accuracy rather than computing speed. In order to drive another order of magnitude of acceleration, we share a benchmark dataset consisting of 200 million 3D complex structures and 2D structure scores across a consistent set of 13 million “in-stock” molecules over 15 receptors, or binding sites, across the SARS-CoV-2 proteome. We believe this is strong evidence for the community to begin focusing on improving the accuracy of surrogate models to improve the ability to screen massive compound libraries 100 × or even 1000 × faster than current techniques and reduce missing top hits. The technique outlined aims to be a fast drop-in replacement for docking for screening billion-scale molecular libraries.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Transition between protein-like and polymer-like dynamic behavior: Internal friction in unfolded apomyoglobin depends on denaturing conditions

Equilibrium dynamics of different folding intermediates and denatured states is strongly connected to the exploration of the conformational space on the nanosecond time scale and might have implications in understanding protein folding. For the first time, the same protein system apomyoglobin has been investigated using neutron spin-echo spectroscopy in different states: native-like, partially folded (molten globule) and completely unfolded, following two different unfolding paths: using acid or guanidinium chloride (GdmCl). While the internal dynamics of the native-like state can be understood using normal mode analysis based on high resolution structural information of myoglobin, for the unfolded and even for the molten globule states, models from polymer science are employed. The Zimm model accurately describes the slowly-relaxing, expanded GdmCl-denaturated state, ignoring the individuality of the different aminoacid side chain. The dynamics of the acid unfolded and molten globule state are similar in the framework of the Zimm model with internal friction, where the chains still interact and hinder each other: the first Zimm relaxation time is as large as the internal friction time. Transient formation of secondary structure elements in the acid unfolded and presence of α-helices in the molten globule state lead to internal friction to a similar extent.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2025

Depletion of the Protein Hydration Shell with Increasing Temperature Observed by Small-Angle X-ray Scattering and Molecular Simulations

The hydration shell is an integral part of proteins since it plays key roles in conformational transitions, molecular recognition, and enzymatic activity. While the dynamics of the hydration shell have been described by spectroscopic techniques, the structure of the hydration shell remains less understood due to the lack of hydration shell-sensitive structural probes with high spatial resolution. We combined temperature-ramp small-angle X-ray scattering (T-ramp SAXS) from 255 to 335 K with molecular simulations to demonstrate that the hydration shells of the IgG-binding domain of Protein G (GB3) and the villin headpiece are remarkably temperature-sensitive. For proteins in the folded state, T-ramp SAXS data and explicit-solvent SAXS predictions consistently demonstrate decays of protein contrasts and radii of gyration with increasing temperature, which are shown to reflect predominantly temperature-sensitive, depleting hydration shells. The depletion is caused not merely by enhanced disorder within the hydration shells but also by partial displacements of surface-coordinated water molecules. Together, T-ramp SAXS and explicit-solvent SAXS calculations provide a novel structural view of the protein hydration shell, which underlies temperature-dependent processes such as cold denaturation, thermophoresis, or biomolecular phase separation.

electron density↗
DOE OSTI2024

Programmed cell death regulator BAP2 is required for IRE1-mediated unfolded protein response in Arabidopsis

Environmental and physiological situations can challenge the balance between protein synthesis and folding capacity of the endoplasmic reticulum (ER) and cause ER stress, a potentially lethal condition. The unfolded protein response (UPR) restores ER homeostasis or actuates programmed cell death (PCD) when ER stress is unresolved. The cell fate determination mechanisms of the UPR are not well understood, especially in plants. Here, we integrate genetics and ER stress profiling with natural variation and quantitative trait locus analysis of 350 natural accessions of the model species Arabidopsis thaliana . Our analyses implicate a single nucleotide polymorphism to the loss of function of the general PCD regulator BON-ASSOCIATED PROTEIN2 (BAP2) in UPR outcomes. We establish that ER stress-induced BAP2 expression is antagonistically regulated by the UPR master regulator, inositol-requiring enzyme 1 (IRE1), and that BAP2 controls adaptive UPR amplitude in ER stress and ignites pro-death mechanisms in conditions of UPR insufficiency.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Molecular chaperone RAP interacts with LRP1 in a dynamic bivalent mode and enhances folding of ligand-binding regions of other LDLR family receptors

The low-density lipoprotein receptor (LDLR) family of receptors are cell-surface receptors that internalize numerous ligands and play crucial role in various processes, such as lipoprotein metabolism, hemostasis, fetal development, etc. Previously, receptor-associated protein (RAP) was described as a molecular chaperone for LDLR-related protein 1 (LRP1), a prominent member of the LDLR family. We aimed to verify this role of RAP for LRP1 and two other LDLR family receptors, LDLR and vLDLR, and to investigate the mechanisms of respective interactions using a cell culture model system, purified system, and in silico modelling. Upon coexpression of RAP with clusters of the ligand-binding complement repeats (CRs) of the receptors in secreted form in insect cells culture, the isolated proteins had increased yield, enhanced folding, and improved binding properties compared with proteins expressed without RAP, as determined by circular dichroism and surface plasmon resonance. Within LRP1 CR-clusters II and IV, we identified multiple sites comprised of adjacent CR doublets, which provide alternative bivalent binding combinations with specific pairs of lysines on RAP. Mutational analysis of these lysines within each of isolated RAP D1/D2 and D3 domains having high affinity to LRP1 and of conserved tryptophans on selected CR-doublets of LRP1, as well as in silico docking of a model LRP1 CR-triplet with RAP, indicated a universal role for these residues in interaction of RAP and LRP1. Consequently, we propose a new model of RAP interaction with LDLR family receptors based on switching of the bivalent contacts between molecules over time in a dynamic mode.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

A General Framework to Learn Tertiary Structure for Protein Sequence Characterization

During the past five years, deep-learning algorithms have enabled ground-breaking progress towards the prediction of tertiary structure from a protein sequence. Very recently, we developed SAdLSA, a new computational algorithm for protein sequence comparison via deep-learning of protein structural alignments. SAdLSA shows significant improvement over established sequence alignment methods. In this contribution, we show that SAdLSA provides a general machine-learning framework for structurally characterizing protein sequences. By aligning a protein sequence against itself, SAdLSA generates a fold distogram for the input sequence, including challenging cases whose structural folds were not present in the training set. About 70% of the predicted distograms are statistically significant. Although at present the accuracy of the intra-sequence distogram predicted by SAdLSA self-alignment is not as good as deep-learning algorithms specifically trained for distogram prediction, it is remarkable that the prediction of single protein structures is encoded by an algorithm that learns ensembles of pairwise structural comparisons, without being explicitly trained to recognize individual structural folds. As such, SAdLSA can not only predict protein folds for individual sequences, but also detects subtle, yet significant, structural relationships between multiple protein sequences using the same deep-learning neural network. The former reduces to a special case in this general framework for protein sequence annotation.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Thermophilic Chassis-Enabled High-Throughput Selection of a Thermostable Fluorogenic Reporter

Thermostable proteins show increased shelf life and performance at elevated temperatures and under harsh conditions, resulting in lower costs for various industrial and biotechnological applications. However, due to a limited understanding of the relationship between stability and function, protein stabilization remains primarily a trial-and-error approach. Therefore, building a combinatorial library of mutations predicted to improve stability, followed by experimental testing, represents a markedly improved methodology. However, the lack of high-throughput approaches to screen even a moderately sized library presents a major bottleneck in the field. Here, in this study, we use a thermophile, Parageobacillus thermoglucosidasius (Ptherm) to rapidly screen combinatorial libraries consisting of rationally designed thermostabilizing mutations (∼10 3 –10 4 ) of a mesophilic fluorescent reporter, Y-FAST. On a Petri dish, microbial growth at an elevated temperature and exposure to fluorogen yielded several colonies of Ptherm that showed distinct fluorescence at 55 and 68 °C in our two sequentially generated libraries using Rosetta and ProteinMPNN, respectively. The Y-FAST variants isolated from fluorescent colonies were brighter than Y-FAST and showed higher resistance to thermal and chemical denaturation. AlphaFold-predicted structures and MD simulations revealed stability-enhancing salt bridges and hydrogen bond networks in the isolated FAST variants. The moderately thermostable FAST (tsFAST) and hyperstable FAST (hsFAST) were then demonstrated as translation reporters for protein expression and folding at elevated temperatures, such as 55 and 68 °C. Our approach of combinatorial library generation and high-throughput screening in a thermophilic chassis could, in principle, be extended to other proteins fused to these translation reporters. Furthermore, the hsFAST protein is small─half the size of the green fluorescent protein─and does not require oxygen for maturation, making it ideal for engineering extremophilic anaerobes for biosensing and bioconversion.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

A fusion of the Bacteroides fragilis ferrous iron import proteins reveals a role for FeoA in stabilizing GTP-bound FeoB

Iron is an essential element for nearly all organisms, and under anoxic and/or reducing conditions, Fe 2+ is the dominant form of iron available to bacteria. The ferrous iron transport (Feo) system is the primary prokaryotic Fe 2+ import machinery, and two constituent proteins (FeoA and FeoB) are conserved across most bacterial species. However, how FeoA and FeoB function relative to one another remains enigmatic. In this work, we explored the distribution of feoAB operons encoding a fusion of FeoA tethered to the N-terminal, G-protein domain of FeoB via a connecting linker region. We hypothesized that this fusion poises FeoA to interact with FeoB to affect function. To test this hypothesis, we characterized the soluble NFeoAB fusion protein from Bacteroides fragilis, a commensal organism implicated in drug-resistant infections. Using X-ray crystallography, we determined the 1.50-Å resolution structure of BfFeoA, which adopts an SH3-like fold implicated in protein–protein interactions. Using a combination of structural modeling, small-angle X-ray scattering, and hydrogen–deuterium exchange mass spectrometry, we show that FeoA and NFeoB interact in a nucleotide-dependent manner, and we mapped the protein–protein interaction interface. Finally, using guanosine triphosphate (GTP) hydrolysis assays, we demonstrate that BfNFeoAB exhibits one of the slowest known rates of Feo-mediated GTP hydrolysis that is not potassium-stimulated. Importantly, truncation of FeoA from this fusion demonstrates that FeoA–NFeoB interactions function to stabilize the GTP-bound form of FeoB. Taken together, our work reveals a role for FeoA function in the fused FeoAB system and suggests a function for FeoA among prokaryotes.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2021

NMR Spectroscopy for Protein Higher Order Structure Similarity Assessment in Formulated Drug Products

Peptide and protein drug molecules fold into higher order structures (HOS) in formulation and these folded structures are often critical for drug efficacy and safety. Generic or biosimilar drug products (DPs) need to show similar HOS to the reference product. The solution NMR spectroscopy is a non-invasive, chemically and structurally specific analytical method that is ideal for characterizing protein therapeutics in formulation. However, only limited NMR studies have been performed directly on marketed DPs and questions remain on how to quantitively define similarity. Here, NMR spectra were collected on marketed peptide and protein DPs, including calcitonin-salmon, liraglutide, teriparatide, exenatide, insulin glargine and rituximab. The 1D 1 H spectral pattern readily revealed protein HOS heterogeneity, exchange and oligomerization in the different formulations. Principal component analysis (PCA) applied to two rituximab DPs showed consistent results with the previously demonstrated similarity metrics of Mahalanobis distance (D M ) of 3.3. The 2D 1 H- 13 C HSQC spectral comparison of insulin glargine DPs provided similarity metrics for chemical shift difference (Δδ) and methyl peak profile, i.e., 4 ppb for 1 H, 15 ppb for 13 C and 98% peaks with equivalent peak height. Finally, 2D 1 H- 15 N sofast HMQC was demonstrated as a sensitive method for comparison of small protein HOS. The application of NMR procedures and chemometric analysis on therapeutic proteins offer quantitative similarity assessments of DPs with practically achievable similarity metrics.

59 BASIC BIOLOGICAL SCIENCES↗